Volume 3, Issue 1, Pages 9-13 (January 2006)

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Volume 3, Issue 1, Pages 9-13 (January 2006) Mitochondrial medicine: A metabolic perspective on the pathology of oxidative phosphorylation disorders  Jan A. Smeitink, Massimo Zeviani, Douglass M. Turnbull, Howard T. Jacobs  Cell Metabolism  Volume 3, Issue 1, Pages 9-13 (January 2006) DOI: 10.1016/j.cmet.2005.12.001 Copyright © 2006 Elsevier Inc. Terms and Conditions

Figure 1 Mitochondrial energy metabolism Schematic representation of mitochondrial energy metabolism and related pathways. I, II, III, IV, and V, complexes I–V. Complexes II, III, and IV are shown as functionally active dimers. SOD2, superoxide dismutase 2; GPx, gluthatione peroxidase; ANT, adenine nucleotide translocator; TCA, tricarboxylic acid; β-oxidn, β-oxidation; PDH, pyruvate dehydrogenase complex; Ac-CoA, acetyl-CoA; DHODH, dihydroorotate dehydrogenase; GPT, glutamic pyruvic transaminase; LDH, lactate dehydrogenase; AIF, apoptosis inducing factor; CAD, caspase-acitivated DNase; Q, coenzyme Q (ubiquinone); QH2, reduced coenzyme Q (ubiquinol); cred and cox, reduced and oxidized forms, respectively, of cytochrome c; ADP, adenosine diphosphate; ATP, adenosine triphosphate; NAD+ and NADH, oxidized and reduced forms, respectively, of nicotinamide adenine dinucleotide, GSH and GS-SG, reduced and oxidized forms, respectively, of glutathione. MtDNA-encoded subunits are shown in blue, membrane transporters in green, the apoptosis-related protein Apaf-1 in cream, other enzymes and pathways in orange. Different metabolic pathways are depicted in different areas of the mitochondrial matrix and inner membrane compartments purely for illustrative purposes. The left-hand area shows Ca2+ transport and the respiratory chain enzymes that are involved in the production of ROS or interacting with other electron carriers, i.e., coenzyme Q and cytochrome c. The middle area shows the main mitochondrial energy pathways. Pyruvate, which stands at the crossroads of glycolysis, gluconeogenesis and OXPHOS, is the key intermediate in carbohydrate oxidation and feeds into the TCA cycle via the pyruvate dehydrogenase complex (PDH) to generate acetyl-CoA. Fatty acids are oxidized within the mitochondrial matrix by β-oxidation, which again generates acetyl-CoA for the TCA cycle. Reducing equivalents generated during the oxidation of the primary substrate or from the TCA cycle are transferred to OXPHOS as NADH (at complex I), or reduced flavins (entering at complex II or III). The right-hand area shows the action of DHODH and its dependence upon coenzyme Q-mediated electron transfer. Components of the mitochondrial apoptotic pathway (AIF, cytochrome c, CAD) are located in the intermembrane space and, upon pro-apoptotic signaling, are released through the permeability transition pore, comprising modified and juxtaposed ANT and porin (VDAC) channels, or via other outer membrane pores, to induce caspase activation in the cytosol. Cell Metabolism 2006 3, 9-13DOI: (10.1016/j.cmet.2005.12.001) Copyright © 2006 Elsevier Inc. Terms and Conditions